MUC1­ND interacts with TRPV1 to promote corneal epithelial cell proliferation in diabetic dry eye mice by partly activating the AKT signaling pathway.

Although both mucin1 (MUC1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) have been reported to be associated with dry eye (DE) disease, whether they interact and their regulatory roles in diabetic DE disease are unknown. Diabetic DE model mice were generated by streptozotocin induction and assessed by corneal fluorescein staining, tear ferning (TF) tests, phenol red thread tests, hematoxylin and eosin staining of corneal sections and periodic acid Schiff staining of conjunctival sections. Cell proliferation was measured by CCK8 assay. Western blotting was performed to measure protein expression. Primary mouse corneal epithelial cells (MCECs) were cultured after enzymatic digestion. Immunofluorescence staining of MCECs and frozen corneal sections was conducted to assess protein expression and colocalization. Coimmunoprecipitation was performed to detect protein­protein interactions. It was found that, compared with control mice, diabetic DE mice exhibited increased corneal epithelial defects, reduced tear production, poorer TF pattern grades and impaired corneal and conjunctival tissues. In vivo and in vitro experiments showed that hyperglycemia impaired cell proliferation, accompanied by decreased levels of the MUC1 extracellular domain (MUC1­ND) and TRPV1. Additionally, it was found that capsazepine (a TRPV1 antagonist) inhibited the proliferation of MCECs. Notably, MUC1­ND was shown to interact with the TRPV1 protein in the control group but not in the diabetic DE group. It was also found that the AKT signaling pathway was attenuated in the diabetic DE mice and downstream of TRPV1. MUC1­ND interacted with TRPV1, partly activating the AKT signaling pathway to promote MCEC proliferation. The present study found that the interaction of MUC1­ND with TRPV1 promotes MCEC proliferation by partly activating the AKT signaling pathway, providing new insight into the pathogenesis of corneal epithelial dysfunction in diabetic DE disease.

Puerarin attenuates remifentanil­induced postoperative hyperalgesia via targeting PAX6 to regulate the transcription of TRPV1.

Remifentanil­induced hyperalgesia (RIH) is characterized by the emergence of stimulation­induced pain, including phenomena such as allodynia and thermal hyperalgesia following remifentanil infusion. As a sequence­specific DNA binding transcription factor, PAX6 positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system. It was hypothesized that puerarin could relieve RIH via targeting PAX6 to regulate transcription of transient receptor potential cation channel subfamily V Member 1 (TRPV1). A total of 32 rats were randomly divided into five groups, namely control group, RI group, RI + 10 mg/kg puerarin group (RI + puerarin10), RI + 20 mg/kg puerarin group (RI + puerarin20), and RI + 40 mg/kg puerarin group (RI + puerarin40). Mechanical and thermal hyperalgesia were tested at ­24, 2, 6, 24 and 48 h after remifentanil infusion. Following the sacrifice of rats after the last behavioral test, western blot was used to detect the expression levels of TRPV1 in the tissues; Immunofluorescence staining and western blotting were used to detect the expression of PAX6 in the spinal cord. PharmMapper and JASPAR were used to predict the binding sites of puerarin/PAX6/TRPV1. Chromatin immunoprecipitation­PCR and dual luciferase reporter assay were used to verify the targeting relationship between PAX6 and TRPV1. Immunofluorescence was used to detect the expression levels of TRPV1 and p­NR2B. The results revealed that puerarin (10, 20, 40 mg/kg) dose­dependently reduced thermal and mechanical hyperalgesia from 2 to 48 h after remifentanil infusion. Remifentanil infusion remarkably stimulated the expression of phosphorylated (p­)NR2B. Nevertheless, the increased amount of p­NR2B by RIH was dose­dependently suppressed by puerarin in rats. In conclusion, puerarin was revealed to attenuate postoperative RIH via targeting PAX6 to regulate the transcription of TRPV1.

Pharmacological activity of capsaicin: Mechanisms and controversies (Review).

Capsaicin, which is abundant in chili peppers, exerts antioxidative, antitumor, antiulcer and analgesic effects and it has demonstrated potential as a treatment for cardiovascular, gastrointestinal, oncological and dermatological conditions. Unique among natural irritants, capsaicin initially excites neurons but then 'calms' them into long­lasting non­responsiveness. Capsaicin can also promote weight loss, making it potentially useful for treating obesity. Several mechanisms have been proposed to explain the therapeutic effects of capsaicin, including antioxidation, analgesia and promotion of apoptosis. Some of the mechanisms are proposed to be mediated by the capsaicin receptor (transient receptor potential cation channel subfamily V member 1), but some are proposed to be independent of that receptor. The clinical usefulness of capsaicin is limited by its short half­life. The present review provided an overview of what is known about the therapeutic effects of capsaicin and the mechanisms involved and certain studies arguing against its clinical use were mentioned.

Transient receptor potential cation channel subfamily V member 1 (TRPV1) targeted PET imaging.

Transient receptor potential cation channel subfamily V member 1 (TRPV1) was identified using capsaicin, a pungent compound that is present in red pepper. The activation of TRPV1 induces an influx of calcium ions into cells and causes excitation of sensory neurons, associating with thermal sensing, sweating and pain. TRPV1 is also identified in various types of cancer cells. The expression of TRPV1 in cancer cells depends on the type of cancer and the stage of the disease. Therefore, TRPV1 has been considered a potential target of medicinal chemistry for drug development, and blocking its activation may lead to cancer therapy and pain relief. However, the details of the pathophysiological function of TRPV1 in vivo are still unclear. To explore practical use of TRPV1, we focused on positron emission tomography imaging and developed a 11C-radiolabeled tracer to visualize TRPV1.

Potential mechanism of transient receptor potential cation channel subfamily V member 1 combined with an ATP­sensitive potassium channel in severe preeclampsia.

Severe preeclampsia is one of the most serious obstetric diseases. However, the pathogenesis of the disease is not fully understood. In the present study, placental artery and blood serum was collected from patients with severe preeclampsia, as well as from normal pregnant women. The results of reverse transcription-quantitative (q)PCR, western blotting, and immunohistochemical staining revealed markedly decreased transient receptor potential cation channel subfamily V member 1 (TRPV1), ATP-sensitive potassium channel (KATP) subtype Kir6.1/SUR2B and endothelial nitric oxide synthase (eNOS) expression in severe preeclampsia tissue specimens compared with those in samples from normal pregnant women. The nitrate reduction method indicated lower NO levels in the tissue specimens and serum of patients with severe preeclampsia. Moreover, hematoxylin-eosin staining showed that the endothelial cell layer in the placental artery of patients with severe preeclampsia was notably damaged. To investigate the potential role of TRPV1-KATP channels in severe preeclampsia, HUVECs were used for in vitro experiments. The samples were divided into a control group, a TRPV1 agonist group (capsaicin) and a TRPV1 inhibitor group (capsazepine). qPCR and western blotting revealed that the relative gene and protein expression levels of TRPV1, Kir6.1, SUR2B and eNOS in the control group were significantly lower than those in the capsaicin group and considerably higher than those in the capsazepine group. Based on previous studies and the results of the present study, we hypothesized that impairment of the endothelial TRPV1-KATP channels results in decreased eNOS/NO pathway activity, which may be one of the mechanisms involved in severe preeclampsia. The increase in NO generation mediated by TRPV1-KATP may be a suitable target for the management of severe preeclampsia.

Endocannabinoid signaling in microglia.

Microglia, the innate immune cells of the central nervous system (CNS), execute their sentinel, housekeeping and defense functions through a panoply of genes, receptors and released cytokines, chemokines and neurotrophic factors. Moreover, microglia functions are closely linked to the constant communication with other cell types, among them neurons. Depending on the signaling pathway and type of stimuli involved, the outcome of microglia operation can be neuroprotective or neurodegenerative. Accordingly, microglia are increasingly becoming considered cellular targets for therapeutic intervention. Among signals controlling microglia activity, the endocannabinoid (EC) system has been shown to exert a neuroprotective role in many neurological diseases. Like neurons, microglia express functional EC receptors and can produce and degrade ECs. Interestingly, boosting EC signaling leads to an anti-inflammatory and neuroprotective microglia phenotype. Nonetheless, little evidence is available on the microglia-mediated therapeutic effects of EC compounds. This review focuses on the EC signals acting on the CNS microglia in physiological and pathological conditions, namely on the CB1R, CB2R and TRPV1-mediated regulation of microglia properties. It also provides new evidence, which strengthens the understanding of mechanisms underlying the control of microglia functions by ECs. Given the broad expression of the EC system in glial and neuronal cells, the resulting picture is the need for in vivo studies in transgenic mouse models to dissect the contribution of EC microglia signaling in the neuroprotective effects of EC-derived compounds.

Transient Receptor Potential Channels, Natriuretic Peptides, and Angiotensin Receptor-Neprilysin Inhibitors in Patients With Heart Failure.

Heart failure (HF) remains the leading cause of death, morbidity, and medical expenses worldwide. Treatments for HF with reduced ejection fraction have progressed in recent years; however, acute decompensated heart failure remains difficult to treat. The transient receptor potential (TRP) channel family plays roles in various cardiovascular diseases, responding to neurohormonal and mechanical load stimulation. Thus, TRP channels are promising targets for drug discovery, and many studies have evaluated the roles of TRP channels expressed on pain neurons. The natriuretic peptide (NP) family of proteins regulates blood volume, natriuresis, and vasodilation and can antagonize the renin-angiotensin-aldosterone system and participate in the pathogenesis of major cardiovascular diseases, such as HF, coronary atherosclerotic heart disease, and left ventricular hypertrophy. NPs are degraded by neprilysin, and the blood level of NPs has predictive value in the diagnosis and prognostic stratification of HF. In this review, we discuss the relationships between typical TRP family channels (e.g., transient receptor potential cation channel subfamily V member 1 andTRPV1, transient receptor potential cation channel subfamily C member 6) and the NP system (e.g., atrial NP, B-type NP, and C-type NP) and their respective roles in HF. We also discuss novel drugs introduced for the treatment of HF.

Diagnosis and Management of Cirrhotic Cardiomyopathy.

BACKGROUND: Cirrhotic cardiomyopathy refers to the structural and functional changes in the heart leading to either impaired systolic, diastolic, electrocardiographic, and neurohormonal changes associated with cirrhosis and portal hypertension. Cirrhotic cardiomyopathy is present in 50% of patients with cirrhosis and is clinically seen as impaired contractility, diastolic dysfunction, hyperdynamic circulation, and electromechanical desynchrony such as QT prolongation. In this review, we will discuss the cardiac physiology principles underlying cirrhotic cardiomyopathy, imaging techniques such as cardiac magnetic resonance imaging and scintigraphy, cardiac biomarkers, and newer echocardiographic techniques such as tissue Doppler imaging and speckle tracking, and emerging treatments to improve outcomes. METHODS: We reviewed available literature from MEDLINE for randomized controlled trials, cohort studies, cross-sectional studies, and real-world outcomes using the search terms "cirrhotic cardiomyopathy," "left ventricular diastolic dysfunction," "heart failure in cirrhosis," "liver transplantation," and "coronary artery disease". RESULTS: Cirrhotic cardiomyopathy is associated with increased risk of complications such as hepatorenal syndrome, refractory ascites, impaired response to stressors including sepsis, bleeding or transplantation, poor health-related quality of life and increased morbidity and mortality. The evaluation of cirrhotic cardiomyopathy should also guide the feasibility of procedures such as transjugular intrahepatic portosystemic shunt, dose titration protocol of betablockers, and liver transplantation. The use of targeted heart rate reduction is of interest to improve cardiac filling and improve the cardiac output using repurposed heart failure drugs such as ivabradine. Liver transplantation may also reverse the cirrhotic cardiomyopathy; however, careful cardiac evaluation is necessary to rule out coronary artery disease and improve cardiac outcomes in the perioperative period. CONCLUSION: More data are needed on the new diagnostic criteria, molecular and biochemical changes, and repurposed drugs in cirrhotic cardiomyopathy. The use of advanced imaging techniques should be incorporated in clinical practice.

Persistent Diarrhea and Eosinophilic Esophagitis Resulting From Chronic Cannabidiol Usage for Refractory Epilepsy.

Cannabidiol is used in the care of treatment-resistant epilepsy. It has been associated with varying side effects, ranging from somnolence to diarrhea and weight loss. We present a patient on chronic cannabidiol therapy who had persistent diarrhea, abdominal pain, weight loss, and esophageal eosinophilia that improved with cannabidiol dose adjustment.

Human TRPV1 and TRPA1 are receptors for bacterial quorum sensing molecules.

In this study, we investigated the activation of TRPV1 and TRPA1 by N-acyl homoserine lactones, quorum sensing molecules produced by Gram-negative bacteria, and the inhibitory effect of TRPV1 and TRPA1 by autoinducing peptides (AIPs), quorum sensing molecules produced by Gram-positive bacteria, using human embryonic kidney 293T cell lines stably expressing human TRPV1 and TRPA1, respectively. As a result, we found that some N-acyl homoserine lactones, such as N-octanoyl-L-homoserine lactone (C8-HSL), N-nonanoyl-L-homoserine lactone (C9-HSL) and N-decanoyl-L-homoserine lactone (C10-HSL), activated both TRPV1 and TRPA1. In addition, we clarified that some N-acyl homoserine lactones, such as N-3-oxo-dodecanoyl-L-homoserine lactone (3-oxo-C12-HSL), only activated TRPV1 and N-acyl homoserine lactones having saturated short acyl chain, such as N-acetyl-L-homoserine lactone (C2-HSL) and N-butyryl-L-homoserine lactone (C4-HSL), only activated TRPA1. Furthermore, we found that an AIP, simple linear peptide CHWPR, inhibited both TRPV1 and TRPA1 and peptide having thiolactone ring DICNAYF, the thiolactone ring were formed between C3 to F7, strongly inhibited only the TRPV1. Although the specificity of TRPV1 and TRPA1 for quorum sensing molecules was different, these data suggest that both TRPV1 and TRPA1 would function as receptors for quorum sensing molecule produced by bacteria. Graphical Abstract.

Comparative effects of capsaicin in chronic obstructive pulmonary disease and asthma (Review).

Chronic obstructive pulmonary disease (COPD) and asthma are chronic respiratory diseases with high prevalence and mortality that significantly alter the quality of life in affected patients. While the cellular and molecular mechanisms engaged in the development and evolution of these two conditions are different, COPD and asthma share a wide array of symptoms and clinical signs that may impede differential diagnosis. However, the distinct signaling pathways regulating cough and airway hyperresponsiveness employ the interaction of different cells, molecules, and receptors. Transient receptor potential cation channel subfamily V member 1 (TRPV1) plays a major role in cough and airway inflammation. Consequently, its agonist, capsaicin, is of substantial interest in exploring the cellular effects and regulatory pathways that mediate these respiratory conditions. Increasingly more studies emphasize the use of capsaicin for the inhalation cough challenge, yet the involvement of TRPV1 in cough, bronchoconstriction, and the initiation of inflammation has not been entirely revealed. This review outlines a comparative perspective on the effects of capsaicin and its receptor in the pathophysiology of COPD and asthma, underlying the complex entanglement of molecular signals that bridge the alteration of cellular function with the multitude of clinical effects.

Resilience to capsaicin-induced mitochondrial damage in trigeminal ganglion neurons.

Capsaicin is an agonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). Strong TRPV1 stimulation with capsaicin causes mitochondrial damage in primary sensory neurons. However, the effect of repetitive and moderate exposure to capsaicin on the integrity of neuronal mitochondria remains largely unknown. Our electron microscopic analysis revealed that repetitive stimulation of the facial skin of mice with 10 mM capsaicin induced short-term damage to the mitochondria in small-sized trigeminal ganglion neurons. Further, capsaicin-treated mice exhibited decreased sensitivity to noxious heat stimulation, indicating TRPV1 dysfunction, in parallel with the mitochondrial damage in the trigeminal ganglion neurons. To analyze the capsaicin-induced mitochondrial damage and its relevant cellular events in detail, we performed cell-based assays using TRPV1-expressing PC12 cells. Dose-dependent capsaicin-mediated mitochondrial toxicity was observed. High doses of capsaicin caused rapid destruction of mitochondrial internal structure, while low doses induced mitochondrial swelling. Further, capsaicin induced a dose-dependent loss of mitochondria and autophagy-mediated degradation of mitochondria (mitophagy). Concomitantly, transcriptional upregulation of mitochondrial proteins, cytochrome c oxidase subunit IV, Mic60/Mitofilin, and voltage-dependent anion channel 1 was observed, which implied induction of mitochondrial biogenesis to compensate for the loss of mitochondria. Collectively, although trigeminal ganglion neurons transiently exhibit mitochondrial damage and TRPV1 dysfunction following moderate capsaicin exposure, they appear to be resilient to such a challenge. Our in vitro data show a dose-response relationship in capsaicin-mediated mitochondrial toxicity. We postulate that induction of mitophagy and mitochondrial biogenesis in response to capsaicin stimulation play important roles in repairing the damaged mitochondrial system.

Electroacupuncture reduces fibromyalgia pain by downregulating the TRPV1-pERK signalling pathway in the mouse brain.

BACKGROUND: Acupuncture has been clinically recommended as a method of pain relief by the World Health Organization and is widely used by medical doctors. Fibromyalgia (FM) pain has a complex physiological and psychological origin and can be pharmacologically treated with duloxetine, milnacipran and pregabalin. However, these drugs produce undesirable side effects, such as headaches, nausea and diarrhoea. Acupuncture may serve as an effective alternative treatment for pain relief with few side effects. AIMS: We hypothesised that acupuncture would reduce FM pain by influencing transient receptor potential cation channel subfamily V member 1 (TRPV1) and the downstream phosphorylated extracellular signal-regulated kinases (pERK), which are located in the central thalamus, amygdala and cortex. METHODS: A FM mouse model was established by injecting two doses of acid saline into 32 female C57/B6 mice. The mice were then assigned to different subgroups (n=8 each) and treated with electroacupuncture (EA) or EA sham control. TRPV1 and pERK expression levels were measured using Western blotting and immunohistochemistry. RESULTS: Our results demonstrated that the expression of TRPV1 and pERK in the thalamus, amygdala and somatosensory cortex was normal in the control mice, but significantly increased in FM mice; these FM-induced changes in expression were attenuated by EA. CONCLUSION: Our data suggest that EA can reverse the central sensitisation of the TRPV1-ERK signalling pathway in the mouse brain. Thus, our findings provide mechanistic evidence supporting the potential therapeutic efficacy of EA for treating FM pain.

Capsaicin: Plants of the Genus Capsicum and Positive Effect of Oriental Spice on Skin Health.

BACKGROUND: Capsaicin, the main pungent ingredient in hot chili peppers, causes excitation of small sensory neurons. It also provides the basic pungent flavor in Capsicum fruits. SUMMARY: Capsaicin plays a vital role as an agonist for the TRPV1 (transient receptor potential cation channel, subfamily V, member 1) receptor. TRPV1 is essential for the reduction of oxidative stress, pain sensations, and inflammation. Therefore, it has many pros related to health issue. Activation and positive impact of TRPV1 via capsaicin has been studied in various dermatological conditions and in other skin-related issues. Past studies documented that capsaicin plays a vital role in the prevention of atopic dermatitis as well as psoriasis. Moreover, TRPV1 is also very important for skin health because it acts as a capsaicin receptor. It is found in nociceptive nerve fibers and nonneural structures. It prompts the release of a compound that is involved in communicating pain between the spinal cord nerves and other parts of the body. Key Messages: Here, we summarize the growing evidence for the beneficial role of capsaicin and TRPV1 and how they help in the relief of skin diseases such as inflammation, permeation, dysfunction, atopic dermatitis, and psoriasis and in pain amplification syndrome.

A distinct structural mechanism underlies TRPV1 activation by piperine.

Piperine, the principle pungent compound in black peppers, is known to activate the capsaicin receptor TRPV1 ion channel. How piperine interacts with the channel protein, however, remains unclear. Here we show that piperine binds to the same ligand-binding pocket as capsaicin but in different poses. There was no detectable detrimental effect when T551 and E571, two major sites known to form hydrogen bond with capsaicin, were mutated to a hydrophobic amino acid. Computational structural modeling suggested that piperine makes interactions with multiple amino acids within the ligand binding pocket, including T671 on the pore-forming S6 segment. Mutations of this residue could substantially reduce or even eliminate piperine-induced activation, confirming that T671 is an important site. Our results suggest that the bound piperine may directly interact with the pore-forming S6 segment to induce channel opening. These findings help to explain why piperine is a weak agonist, and may guide future efforts to develop novel pharmaceutical reagents targeting TRPV1.

Role of transient receptor potential cation channel subfamily V member 1 (TRPV1) on ozone-exacerbated allergic asthma in mice.

Around the globe, worsening air pollution is spawning major public health and environmental concerns, especially in the poorest and most populous cities. As a major secondary air pollutant, ozone is a potential risk factor for exacerbated asthma, although the underlying mechanisms remain uncertain. In this study, we aim to investigate the role of ozone on asthma exacerbation using a classic asthmatic model with allergic airway inflammation by treating Balb/c mice with ovalbumin (OVA). Our study shows ozone exposure significantly exacerbated OVA-induced asthmatic phenotypes, including serum immunoglobulin, Th cytokines, inflammatory cell counts, mucus production, airway remodeling, and airway hyper-responsiveness (AHR). Interestingly, expression of transient receptor potential cation channel subfamily V member1 (TRPV1) was also significantly elevated in ozone-exacerbated asthmatic mice and that treatment with TRPV1 antagonist effectively suppressed AHR, airway inflammation and remodeling. The underlying mechanisms of these effects may be associated with suppression of neuropeptide calcitonin gene-related peptide (CGRP) and thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine. Base on the role of TRPV1 in allergic asthma, this study further revealed that inhibition of TRPV1 by TRPV1 antagonist has significant anti-inflammatory effects on ozone-induced asthma exacerbation in this study. Induction of TRPV1 expression may be an important mechanism underlying the increased risks for asthma after exposure to environmental pollutants.

Effect of cold and hot compress on neutrophilic migration to the site of doxorubicin extravasation.

In the present study, we investigated a part of the mechanism responsible for the effects of hot and cold compresses for extravasation of doxorubicin. We injected 20 µl of doxorubicin (DOX) (1 µg/µl) subcutaneously into the dorsal area in mice and observed the resulting skin lesions macroscopically and histologically from day 1 to day 14 thereafter in groups treated with a cold pack (18-20°C) and a hot pack (38-40°C) or left untreated (control). Immunofluorescence and RT-PCR for C5a receptor (CD88), interleukin-8 receptor (IL-8RA), and transient receptor potential cation channel subfamily V member 1 (TRPV1) were also performed. Macroscopic observation showed that the area of the skin lesion was significantly smaller in the cold group than in the control group, but was significantly larger in the hot group. The neutrophil count in the lesion was significantly higher in the hot group than in the cold (3 hrs) and control groups. The numbers of inflammatory cells expressing CD88 and IL-8RA were significantly lower in the cold group than that in the other groups at almost time points and in the hot groups at later time points, respectively. The number of nerve fascicles expressing TRPV1 was higher in the hot group than in the cold group on days 1, 3 and 14. mRNA for CD88, IL-8RA and TRPV1 was detectable by reverse transcription-polymerase chain reaction in both the cold and hot pack groups. Consequently, these results suggested that the cold pack for the extravasation of DOX might reduce inflammation.

Association of cough hypersensitivity with tracheal TRPV1 activation and neurogenic inflammation in a novel guinea pig model of citric acid-induced chronic cough.

Objective This study was performed to establish a novel model of citric acid-induced chronic cough in guinea pigs and to investigate the pathogenesis of cough hypersensitivity. Methods Healthy conscious guinea pigs inhaled citric acid (0.4 M) for 3 minutes twice daily for 25 days. Cough reactivity was evaluated, substance P (SP) and calcitonin gene-related peptide (CGRP) in bronchoalveolar lavage fluid were detected, and transient receptor potential cation channel subfamily V member 1 (TRPV1) protein expression in the trachea and bronchus was determined. Tracheal and bronchial tissues were examined for TRPV1. Results Inhalation of 0.4 M citric acid increased coughing in a time-dependent manner: coughing peaked at 15 days and reached the lowest level at 25 days. This was accompanied by similar changes in SP, CGRP, and TRPV1 protein expression. TRPV1 was mainly observed in the mucosal and submucosal layer of the trachea and bronchi. The areas of TRPV1 positivity in the trachea and bronchi of citric acid-treated animals were significantly larger than in the control group. Conclusions Repeated inhalation of citric acid can be employed to establish a chronic cough model in guinea pigs. Cough hypersensitivity in this model is related to tracheal TRPV1 activation and neurogenic inflammation.

Sensitization of TRPV1 receptors by TNF-α orchestrates the development of vincristine-induced pain.

Vincristine is one of the most common anticancer drugs clinically employed in the treatment of various malignancies. A major side effect associated with vincristine is the development of neuropathic pain, which is not readily relieved by available analgesics. Although efforts have been made to identify the pathogenesis of vincristine-induced neuropathic pain, the mechanisms underlying its pathogenesis have not been fully elucidated. In the present study, a neuropathic pain model was established in Sprague-Dawley rats by intraperitoneal injection of vincristine sulfate. The results demonstrated that vincristine administration induced the upregulation of transient receptor potential cation channel subfamily V member 1 (TRPV1) protein expression and current density in dorsal root ganglion (DRG) nociceptive neurons. Consistently, inhibition of TRPV1 with capsazepine alleviated vincristine-induced mechanical allodynia and thermal hyperalgesia in rats. Furthermore, vincristine administration induced the upregulation of tumor necrosis factor (TNF)-α production in DRGs, and inhibition of TNF-α synthesis with thalidomide in vivo reversed TRPV1 protein expression, as well as pain hypersensitivity induced by vincristine in rats. The present results suggested that TNF-α could sensitize TRPV1 by promoting its expression, thus leading to mechanical allodynia and thermal hyperalgesia in vincristine-treated rats. Taken together, these findings may enhance our understanding of the pathophysiological mechanisms underlying vincristine-induced pain.

CGRPα within the Trpv1-Cre population contributes to visceral nociception.

The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRPα is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRPα from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRPα-mCherrylx/lx;Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRPα-mCherrylx/lx;Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRPα-mCherrylx/lx;Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRPα-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRPα- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor potential cation channel subfamily V member 1 (TRPV1)-expressing primary afferent neurons, but the functional role of CGRPα specifically in these neurons is unknown in pain processing from visceral and somatic afferents. We used cre-lox recombination to conditionally delete CGRPα from TRPV1-expressing neurons in mice. We show that CGRPα from within TRPV1-cre population plays an important role in visceral nociception but less so in somatic nociception.